Stem cells are undifferentiated cells that have the capacity to differentiate into two or more cell types with self-renewal capacity. Based on differentiation potency, stem cells can be classified into totipotent stem cells, pluripotent stem cells, and multipotent stem cells. Based on biological origin, in addition, stem cells can be classified into embryonic stem cells and adult stem cells. Embryonic stem cells are derived from preimplantation embryos, developing fetal reproductive organs, and the like, whereas adult stem cells are derived from an individual organ, e.g., bone marrow, brain, liver, pancreas, or the like, of adults.
Totipotent stem cells are cells that have the ability to differentiate into any cell in an organism. Totipotency is maintained until the 8-cell stage after fertilization, occurring when a sperm fuses with an egg. Totipotent stem cells can be isolated and then transplanted into the uterus to develop into an intact individual.
Pluripotent stem cells are cells that have the capacity to differentiate into any types of cells and tissues which constitute ectoderm, mesoderm, or endoderm. Stem cells originate from an inner cell mass, located on the inside of a blastocyst that appears 4 to 5 days after fertilization, and the cells are called embryonic stem cells, which have the capacity to differentiate into multiple types of tissue cells, but have no capacity to develop into a new individual.
Multipotent stem cells are stem cells that have the capacity to differentiate only into specialized cell types in a specific tissue and organ where the stem cells are found. Stem cells play a part in functions that maintain adult tissue homeostasis and induce regeneration in the event of tissue damage, as well as growth and development of respective tissue or organs during fetal, neonatal and adult periods. Particularly, adult stem cells are the general term for such tissue-specific multipotent cells. Adult stem cells are derived from existing cells, which are isolated from various organs of the human body and then developed into stem cells. Interestingly, although adult stem cells have general features to differentiate into specialized cell types of the tissue, recent studies have received attention by showing that adult stem cells can differentiate into various tissue cells, such as liver cells.
Stem cells retain characteristics, such as self-renewing, differentiation, immortality, etc. In particular, adult stem cells, which can be obtained from multiple tissues, are widely used in research, because the cells are generally harvested from unlimited sources and avoid the ethical issues with which researchers may be faced when using embryonic stem cells.
Recently, preclinical and clinical research to apply stem cells to various diseases, such as cerebral infarctions, traumatic brain injuries, and musculoskeletal diseases, is underway. However, technologies pertaining to stem cell therapies currently have limitations, only focusing on isolating and culturing/proliferating stem cells, and injection thereof. In addition, recent clinical research results showed that such stem cell therapies do not exhibit distinct effects yet. Accordingly, research using various gene-modified stem cells to increase therapeutic effects is underway. However, application of cell therapy, in which genes are modified, to the human body is limited due to ethical problems.
In addition, there are several problems in applying therapeutic methods using stem cells to clinical trials. For example, tumor masses may be formed after engraftment of stem cells to organs, and cerebral infarction may occur due to an artery occlusion likely induced by the large size of stem cell itself. The stem cells easily move into the brain when the brain-blood vessel barrier is open as in an acute stage. However, in a chronic stage, movement of the stem cells is limited due to large sizes thereof.
Meanwhile, an exosome is a small vesicle with a membrane structure secreted from a variety of cell types. Exosomes reportedly have a diameter of about 30-100 nm. It was observed that exosomes were derived from specific intracellular parts called multivesicular bodies (MVBs) and released and secreted to the outside of cells, instead of being directly detached and released from plasma membranes, by means of an electron microscope. That is, when fusion between multivesicular bodies and plasma membranes occurs, vesicles are released to the outside of cells. These vesicles are called exosomes. Although a molecular mechanism for a formation process of such exosomes is not clearly determined, it is known that a variety of immunocytes including B lymphocytes, T lymphocytes, dendritic cells, platelets, macrophages, etc., tumor cells, and stem cells, as well as red blood cells, produce and secret exosomes during their lifespan. In particular, it is known that, since stem cell-derived exosomes contain nuclear components as well as receptors and proteins, the exosomes play roles in intercellular communication. In addition, since stem cell-derived exosomes contain a relatively small amount of animal serum, compared to stem cells, the risk of symptoms (zoonosis) due to infection caused by animal serum can also be eliminated. Considering such characteristics of exosomes, it is anticipated that cytotherapy using exosomes can be a new paradigm to overcome the limitations of existing stem cell therapies.
Meanwhile, inflammatory brain diseases refer to inflammatory diseases that occur in the brain by specific causes, and the diseases include encephalitis, encephalomeningitis, and meningoencephalitis, etc. Encephalitis is a general term for inflammatory diseases of the cerebral parenchyma and is different from the inflammation (e.g., encephalomeningitis) that occurs in cerebral meninges surrounding the brain. Meningoencephalitis is a medical condition wherein both encephalomeningitis and encephalitis exist simultaneously. Based on cause, encephalitis can be generally classified into infectious, vasculitis, neoplastic, chemical, idiopathic, etc., and further classified depending on the specific causes of disease according to each detailed item. Additionally, encephalitis can be also classified into acute, subacute, and chronic encephalitis depending on the elapsed time of disease. Up to now, antibiotic treatment is used as the method to treat the inflammatory brain diseases. However, although the causative agents of diseases may be eliminated by antibiotic treatment, side effects, including serious brain damage, hydrocephalus, hearing loss, epilepsy, etc., can occur due to use of antibiotics. Thus, development of new therapeutics is required. However, until now, treatments using stem cell-derived exosomes for inflammatory brain diseases have not been systemically studied.
The present inventors have been continuing research on development of a new therapeutic agent for treating inflammatory brain diseases. As a result, the present inventors demonstrated that stem cell-derived exosomes inhibit cell death due to inflammation in nerve cells, and showed that the exosomes have outstanding therapeutic effects in an inflammatory-brain-disease animal model, thus completing the present invention.